ArticleCell death and differentiation2026
Targeting MMA-induced USP36 methylmalonylation to suppress macrophage polarization and tumor progression in clear-cell renal cell carcinoma.
Article in Cell death and differentiation, 2026. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 4 papers.
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4 citing papers in PubMed.
- Reprogramming the tumor microenvironment: methylmalonic acid at the intersection of ccRCC metabolism and macrophage polarization.Cell death and differentiation · 2026Article
- Loss of lncRNA AK015322 increases sperm morphological abnormalities and impairs motility in mice.Molecular and cellular biochemistry · 2026Article
- Mitochondrial Proteins in Putative Neuron-Derived Plasma Exosomes Are Altered in Parkinson's Disease: An Exploratory Study.Molecular neurobiology · 2026Article
- Nuclear receptor corepressor 1 is a potential diagnostic and prognostic biomarker in clear cell renal cell carcinoma.Scientific reports · 2026Article
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10 authors.
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Abstract
Metabolic reprogramming is a hallmark of clear-cell renal cell carcinoma (ccRCC), driving tumor progression and altering the tumor microenvironment (TME), making it crucial to understand metabolic dysregulation in ccRCC and to identify new therapeutic targets for patients. In this study, metabolomic profiling identified elevated levels of methylmalonic acid (MMA) in ccRCC, attributed to downregulation of methylmalonyl-CoA mutase (MMUT). MMA produced by ccRCC accumulates in the TME and activates the suppressor of fused (SUFU)-regulated Hedgehog signaling pathway in a dose-dependent manner, promoting M2 polarization of macrophages and tumor progression. Mechanistically, MMA induces methylmalonylation at the K499 site of ubiquitin-specific peptidase 36 (USP36), inhibiting USP36-mediated deubiquitination and SUMOylation of SUFU, thereby promoting the expression of GLI family zinc finger 1 (GLI1) and its target genes. Both in vitro and in vivo experiments demonstrated that a low branched-chain amino acids (BCAAs) diet or treatment with the de-methylmalonylation agent MC3138 effectively inhibited M2 polarization of macrophages and tumor progression. These findings emphasize the critical role of MMA in ccRCC pathogenesis and suggest that combining a low-BCAAs diet with MC3138 therapy may offer a promising treatment strategy for ccRCC patients with elevated MMA levels.
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